Structural characterization of PaFkbA: A periplasmic chaperone from Pseudomonas aeruginosa

Huang, Qin; Yang, Jing; Li, Changcheng; Song, Yingjie; Zhu, Yuanfeng; Zhao, Ninglin; Mou, Xingyu; Tang, Xinyue; Luo, Guihua; Tong, Aiping; Sun, Binyong; Tang, Hong; Li, Hong; Bai, Lang; Bao, Rui

doi:10.1016/j.csbj.2021.04.045

Cited by 6 publications

(4 citation statements)

References 46 publications

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“…Intrinsic structural flexibility seems to be a hallmark of homodimeric MIP proteins from pathogenic microorganisms [42]. Not only did we notice significant stalk helix splaying between the two available crystal structures of full-length LpMIP in the absence of a ligand, but a recently published structure of unliganded, homodimeric P. aeruginosa FkbA, which shares the same three-domain architecture, showed both straight and bent stalk helices in the crystal structure [25]. It has been suggested that variations in crystal structures are a good proxy for dynamics in solution [43] and in the case of LpMIP, we can support and extend this notion with EPR and NMR spectroscopy as well as SAXS.…”

Section: Discussionmentioning

confidence: 59%

“…MIP proteins are widely expressed in many other human pathogenic microorganisms such as Chlamydia spp. [22], Neisseria gonorrhoeae [23], the entero-pathogen Salmonella typhimurium [24], Pseudomonas aeruginosa [25], and intracellular parasitic protozoans such as Trypanosoma cruzi, the causative agent of Chagas disease in South and Central America [26][27][28]. Hence, the PPIase domains of MIP proteins are attractive antimicrobial and antiparasitic drug targets [29], however their shallow ligand binding pocket and similarity to human FKBPs render selective drug design challenging [30,31].…”

Section: Introductionmentioning

confidence: 99%

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Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

Wiedemann

Whittaker

Carrillo

et al. 2023

Preprint

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Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens includingLegionella pneumophila, the causative agent of Legionnaires disease and protozoans such asTrypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella protein (LpMIP) have additional appendage domains of mostly unknown function. In full-length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to toL. pneumophilaandT. cruziMIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

Wiedemann

Whittaker

Carrillo

et al. 2023

Preprint

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“…In addition, many of the diseases caused by these pathogens can be chronic as well as severely disabling, thereby placing a tremendous burden on the patients and their caregivers as well as the respective economy and health care infrastructure. A unifying factor in many pathogens with an intracellular lifecycle stage is the presence of MIP virulence factors (35,36). We thus sought to compare the ability of archetypical microbial MIP proteins to interact with inhibitors and to create a roadmap for novel inhibitor design.…”

Section: Discussionmentioning

confidence: 99%

Structure and dynamics of macrophage infectivity potentiator proteins from pathogenic bacteria and protozoans bound to fluorinated pipecolic acid inhibitors

Pérez Carrillo,

Whittaker,

Wiedemann

et al. 2024

Preprint

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Macrophage infectivity potentiator (MIP) proteins are present in many microbial pathogens, both of pro- and of eukaryotic origin. MIP proteins play important roles in microbial virulence, facilitating processes like host cell infection, pathogen replication and dissemination. While their domain architecture differs in MIPs, they all share a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain. Due to its high conservation, the FKBP domain has been a target for inhibitor development, including pipecolic acid derivatives. Here, we determined the high-resolution crystal structures of Burkholderia pseudomallei and Trypanosoma cruzi MIP in complex with fluorinated pipecolic acid inhibitors. Furthermore, we compared the inhibitor binding profiles of MIP proteins from B. pseudomallei, T. cruzi and Legionella pneumophila MIP using 1H, 15N-NMR spectroscopy. Additionally, 19F NMR was used to gauge inhibitor binding to the different MIP proteins. Complementary approaches including EPR spectroscopy and SAXS were used to investigate the global structural changes of homodimeric L. pneumophila MIP upon inhibitor binding. Our data provide a foundation for future inhibitor optimization and advance our understanding of the unexpected dynamic variability within a structurally conserved protein family.

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“…Recently, DegP has been shown to correlate with acid resistance required for food-borne enteric pathogens to pass through the human stomach [38] . P. aeruginosa MucD is believed to be involved in biofilm formation and also influences host neutrophil responses [39] , [40] , [41] .…”

Section: The Versatile Roles Exhibited By Htra Proteins In Bacteriamentioning

confidence: 99%

Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view

Song

Kang

et al. 2022

Computational and Structural Biotechnology Journal

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Members of the high temperature requirement A (HtrA) protein family are widely distributed amongst prokaryotic and eukaryotic species. HtrA proteins have ATP-independent dual chaperone-protease activity and mediate protein quality control. Emerging evidence indicates that HtrA family members are vital for establishing infections and bacterial survival under stress conditions. Bacterial HtrA proteins are increasingly thought of as important new targets for antibacterial drug development. Recent literature suggests that HtrA protein AlgW from Pseudomonas aeruginosa has distinct structural, functional, and regulatory characteristics. The novel dual-signal activation mechanism seen in AlgW is required to modulate stress and drug responses in bacteria, prompting us to review our understanding of the many HtrA proteins found in microorganisms. Here, we describe the distribution of HtrA gene orthologues in pathogenic bacteria, discuss their structure–function relationships, outline the molecular mechanisms exhibited by different bacterial HtrA proteins in bacteria under selective pressure, and review the significance of recently developed small molecule inhibitors targeting HtrA in pathogenic bacteria.

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Structural characterization of PaFkbA: A periplasmic chaperone from Pseudomonas aeruginosa

Cited by 6 publications

References 46 publications

Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

Structure and dynamics of macrophage infectivity potentiator proteins from pathogenic bacteria and protozoans bound to fluorinated pipecolic acid inhibitors

Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view

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